Abstract
BACKGROUND: Chronic ethanol use drives numerous neurological dysfunctions. Ethanol in the brain is mainly metabolized into acetaldehyde by catalase and cytochrome P450 2E1 (Cyp2e1), and acetaldehyde does not freely cross the blood-brain barrier. While Cyp2e1 is a well-known enzyme in liver toxicology, how central nervous system (CNS)-expressed Cyp2e1 contributes to ethanol toxicity is unknown. METHODS: We investigated the effects of Cyp2e1-driven ethanol metabolism in the brain of male and female global Cyp2e1 knockout (KO) and wild-type (WT) 129S1/SvImJ mice. RNA-seq was completed on the medial prefrontal cortex (mPFC), the dorsal and ventral hippocampus, and cerebellum to see whether there are baseline differences in gene expression between WT and KO mice. To investigate acute functional tolerance (AFT), we evaluated blood ethanol concentrations (BECs) of mice on a fixed-speed rotarod after two consecutive ethanol doses. Next, we used the chronic intermittent ethanol (CIE) exposure model to study dependence-induced escalation of drinking. After the study, catalase protein expression was analyzed in the mPFC, hippocampus, and cerebellum. RESULTS: Transcriptomic pathway analysis in ethanol-naïve mice revealed differences in ethanol-important pathways in both male and female Cyp2e1-KO mice. Glyoxylase-1 (Glo1) was downregulated in KO animals. Both WT and Cyp2e1-KO mice had a similar AFT. However, after both injections, Cyp2e1-KO mice had to reach a lower BEC to balance on the rotarod (p < 0.001), indicating increased sensitivity to ethanol intoxication. In the drinking study, Cyp2e1-KO mice drank more than WT controls during baseline drinking sessions (p < 0.01, n = 8-9). After CIE exposure, only Cyp2e1-KO mice significantly escalated their drinking (p < 0.001, n = 16-17). Catalase levels were not significantly higher in KO mice in the brain regions studied regardless of condition. CONCLUSIONS: This study reveals an important role for Cyp2e1 in ethanol-related behaviors and highlights a need to better understand the effects of ethanol and its metabolites in mediating ethanol drinking and sensitivity.